We have presented evidence for the existence of an insulin-sensitive receptor in the CNS. Exposure of this receptor to insulin resulted in immediate reduction of the systemic blood sugar in experimental animals. We have shown that the center regulates the blood sugar by influencing hepatic metabolism, and that the impulse from the CNS reaches the liver directly through the parasympathetic nerves; neither the pituitary nor the pancreas is required for the transmission of the impulse. The sensitivity of the glucoregulator receptor to exogenous insulin correlates inversely to the endogenous steady state insulin levels. In continuing this line of research we wish to investigate: 1) the exact location of the center by chemical destruction (goldthioglucose), stereotaxic lesioning, and radioautographic identification, 2) the influence of other hormones (glucagon, growth hormone, somatostatin administered through the carotid artery) on the sensitivity of the receptor to insulin, 3) the activity of the center under different insulin and glucose concentrations during in situ isolated perfusion of the rat brain, that has intact neural connections to the liver, 4) the role of the insulin-sensitive receptor in the pathogenesis of hyperinsulinemia, obesity, insulin resistance and diabetes mellitus. These will be studied in genetically obese, hyperinsulinemic and in diabetic rodents: a) by investigating the integrity of the neural pathway through which the center influences hepatic metabolism in the above animal models that stimulate human disease states. Selective regional insulinization of the CNS will be performed in rats, dogs and mice in vivo, according to the method established in our laboratory. Changes in peripheral blood sugar, free fatty acids, alpha-aminonitrogen, insulin and growth hormone levels will be studied.